Skip to main content

Advertisement

SpringerLink
Log in

Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients.

Methods

CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses.

Results

Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found.

Conclusion

Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. Clinical trial registration: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

IGF-1R:

Insulin-like growth factor-1 receptor

CTCs:

Circulating tumor cells

MBC:

Metastatic breast cancer

BC:

Breast cancer

IRS-2:

Insulin receptor substrate-2

References

  1. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928. https://doi.org/10.1038/nrc2536

    Article  PubMed  CAS  Google Scholar 

  2. Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like growth factors and neoplasia. Nat Rev Cancer 4:505–518. https://doi.org/10.1038/nrc1387

    Article  PubMed  CAS  Google Scholar 

  3. Pollak MN, Chapman JW, Pritchard KI, Krook JE, Dhaliwal HS, Vandenberg TA et al (2006) Insulin resistance, estimated by serum c-peptide level, is associated with reduced event-free survival for postmenopausal women in the NCIC MA14 adjuvant BC trial. J Clin Oncol 24(Suppl):524. https://doi.org/10.1200/jco.2006.24.18_suppl.524

    Article  Google Scholar 

  4. Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y et al (2002) Fasting insulin and outcome in early-stage BC: results of a prospective cohort study. J Clin Oncol 20:42–51. https://doi.org/10.1200/JCO.2002.20.1.42

    Article  PubMed  CAS  Google Scholar 

  5. Sandhu MS, Dunger DB, Giovannucci EL (2022) Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer. J Natl Cancer Inst 94:972–980. https://doi.org/10.1093/jnci/94.13.972

    Article  Google Scholar 

  6. Sachdev D, Yee D (2007) Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6:1–12. https://doi.org/10.1158/1535-7163.MCT-06-0080

    Article  PubMed  CAS  Google Scholar 

  7. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M (2006) Metformin is an AMP kinase dependent growth inhibitor for BC cells. Cancer Res 66:10269–10273. https://doi.org/10.1158/0008-5472.CAN-06-1500

    Article  PubMed  CAS  Google Scholar 

  8. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A et al (2014) Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res 7:867–885. https://doi.org/10.1158/1940-6207.CAPR-13-0424

    Article  CAS  Google Scholar 

  9. Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A et al (2012) Dual effect of metformin on BC proliferation in a randomized presurgical trial. J Clin Oncol 30:2593–2600. https://doi.org/10.1200/JCO.2011.39.3769

    Article  PubMed  CAS  Google Scholar 

  10. Goodwin PJ, Parulekar WR, Gelmon KA, Shepherd LE, Ligibel JA, Hershman DL et al (2015) Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 107:1–8. https://doi.org/10.1093/jnci/djv006

    Article  CAS  Google Scholar 

  11. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC et al (2004) Circulating tumor cells, disease progression, and survival in metastatic BC. N Engl J Med 351:781–791. https://doi.org/10.1056/NEJMoa040766

    Article  PubMed  CAS  Google Scholar 

  12. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC et al (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic BC patients predict progression-free and overall survival. Clin Cancer Res 12:4218–4224. https://doi.org/10.1158/1078-0432.CCR-05-2821

    Article  PubMed  CAS  Google Scholar 

  13. De Bono J, Attard G, Adjei A, Pollak MN, Fong PC, Haluska P et al (2007) Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor. Clin Cancer Res 13:3611–3616. https://doi.org/10.1158/1078-0432.CCR-07-0268

    Article  PubMed  CAS  Google Scholar 

  14. Bahr C, Groner B (2005) The IGF-1 receptor and its contributions to metastatic tumor growth-novel approaches to the inhibition of IGF-1R function. Growth Factors 23:1–14. https://doi.org/10.1080/08977190400020229

    Article  PubMed  CAS  Google Scholar 

  15. Nanni O, Amadori D, De Censi A, Rocca A, Freschi A, Bologna A et al (2019) Metformin plus chemotherapy versus chemotherapy alone in the first- line treatment of HER2-negative metastatic BC. The MYME randomized, phase 2 clinical trial. BC Res Treat 174:433–442. https://doi.org/10.1007/s10549-018-05070-2

    Article  CAS  Google Scholar 

  16. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419. https://doi.org/10.1007/bf00280883

    Article  PubMed  CAS  Google Scholar 

  17. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Meigs JB et al (1998) Prevalence of insulin resistance in metabolic disorders: the Bruneck study. Diabetes 47:1643–1649. https://doi.org/10.2337/dc06-0919

    Article  PubMed  CAS  Google Scholar 

  18. Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D et al (2014) Clinical validity of circulating tumour cells in patients with metastatic BC: a pooled analysis of individual patient data. Lancet Oncol 15:406–414. https://doi.org/10.1016/S1470-2045(14)70069-5

    Article  PubMed  Google Scholar 

  19. Rossi E, Basso U, Celadin R, Zilio F, Pucciarelli S, Aieta M et al (2010) M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by cell Search analysis. Clin Cancer Res 16:5233–5243. https://doi.org/10.1158/1078-0432.CCR-10-1449

    Article  PubMed  CAS  Google Scholar 

  20. Nakae J, Kido Y, Accili D (2010) Distinct and overlapping functions of insulin and IGF-I receptors. Endocr Rev 22:818–835. https://doi.org/10.1210/edrv.22.6.0452

    Article  Google Scholar 

  21. Iams WT, Lovly CM (2015) Molecular pathways: clinical applications and future direction of insulin-like growth Factor-1 receptor pathway blockade. Clin Cancer Res 21:4270–4277. https://doi.org/10.1158/1078-0432.CCR-14-2518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Cristofanilli M, Pierga JY, Reuben J, Rademaker A, Davis AA, Peeters DJ et al (2019) The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic BC (MBC): international expert consensus paper. Crit Rev Oncol Hematol 134:39–45. https://doi.org/10.1016/j.critrevonc.2018.12.004

    Article  PubMed  Google Scholar 

  23. Pizon M, Zimon DS, Pachmann U, Pachmann K (2013) Insulin-like growth factor receptor I (IGF-IR) and vascular endothelial growth factor receptor 2 (VEGFR-2) are expressed on the circulating epithelial tumor cells of BC patients. PLoS ONE 8:e56836. https://doi.org/10.1371/journal.pone.0056836

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Spiliotaki M, Mavroudis D, Kokotsaki M, Vetsika EK, Stoupis I, Matikas A et al (2018) Expression of insulin-like growth factor-1 receptor in circulating tumor cells of patients with BC is associated with patient outcomes. Mol Oncol 12:21–32. https://doi.org/10.1002/1878-0261.12114

    Article  PubMed  CAS  Google Scholar 

  25. Pennisi PA, Barr V, Nunez NP, Stannard B, Le RD (2002) Reduced expression of insulin-like growth factor I receptors in MCF-7 BC cells leads to a more metastatic phenotype. Cancer Res 62:6529–6537. https://doi.org/10.1210/en.2006-0311

    Article  PubMed  CAS  Google Scholar 

  26. Jones RA, Moorehead RA (2008) The impact of transgenic IGF-IR overexpression on mammary development and tumorigenesis. J Mammary Gland Biol Neoplasia 13:407–413. https://doi.org/10.1007/s10911-008-9097-1

    Article  PubMed  Google Scholar 

Download references

Funding

The TransMYME study was supported by the Italian Association for Cancer Research (AIRC–IG 2009, Project Number 9239).

Author information

Authors and Affiliations

  1. Medical Oncology, Department of Translational Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100, Novara, Italy

    Alessandra Gennari & Veronica Martini

  2. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Flavia Foca & Oriana Nanni

  3. Department of Immunology and Oncological Molecular Diagnostics, Veneto Institute of Oncology (IOV) IRCCS, Padua, Italy

    Rita Zamarchi, Elisabetta Rossi & Antonella Facchinetti

  4. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Andrea Rocca & Dino Amadori

  5. Division of Medical Oncology, EO Ospedali Galliera, Genoa, Italy

    Andrea De Censi

  6. Department of Oncology, Arcispedale S. Maria Nuova IRCCS, Reggio Emilia, Italy

    Alessandra Bologna

  7. Oncology-Hematology Department, Hospital of Piacenza, Piacenza, Italy

    Luigi Cavanna

  8. Department of Medical Oncology, Ospedale Infermi, Rimini, Italy

    Lorenzo Gianni

  9. Oncology Day Hospital Unit, Ospedale Civile Di Guastalla, Guastalla, Italy

    Laura Scaltriti

  10. Department of Surgery, Oncology and Gastroenterology, University of Paduva, Paduva, Italy

    Elisabetta Rossi & Antonella Facchinetti

  11. Department of Clinical Epidemiology, IRCCS San Martino – IST, Genoa, Italy

    Paolo Bruzzi

Authors
  1. Alessandra Gennari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Flavia Foca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rita Zamarchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Rocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dino Amadori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea De Censi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandra Bologna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luigi Cavanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lorenzo Gianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laura Scaltriti
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elisabetta Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Antonella Facchinetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Veronica Martini
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paolo Bruzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Oriana Nanni
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AG, DA, ON, and PB designed and supervised the trial. AG, AR, ADC, AB, LC, LG, LS were responsible for patient recruitment and data collection. FF, ON and PB analyzed the data. AF, ER, and RZ performed CTC tests. The first draft of the manuscript was written by AG, VM, FF, and ON, and the remaining co-authors subsequently provided valuable input. All the authors read and approved the final version of the article. The corresponding author assumes responsibility for the completeness and integrity of data, the study fidelity to the protocol, and the statistical analysis. She had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Alessandra Gennari.

Ethics declarations

Conflict of interests

The authors declare no potential conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gennari, A., Foca, F., Zamarchi, R. et al. Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial. Breast Cancer Res Treat 181, 61–68 (2020). https://doi.org/10.1007/s10549-020-05596-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-020-05596-4

Keywords

Search

Navigation